| Autor: |
Wu, David, Hailer, Ashley A., Wang, Sijia, Yuan, Michelle, Chan, Jamie, El Kurdi, Abdullah, Han, David, Ali, Hira, D'Angio, Blaize, Mayer, Aaron, Rahim, Maha, Kondo, Ayano, Klufas, Daniel, Kim, Esther, Shain, A. Hunter, Choi, Jaehyuk, Bhutani, Tina, Simpson, Gregory, Grekin, Roy C., Ricardo-Gonzalez, Roberto |
| Předmět: |
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| Zdroj: |
Science Immunology; 2024, Vol. 9 Issue 91, p1-12, 12p |
| Abstrakt: |
Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17–producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade–responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17–induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments. Editor's summary: Although the underlying cause of psoriasis is not completely understood, therapies that suppress the activity of IL-17–producing T (T17) cells have achieved broad clinical success. Using single-cell transcriptomics of skin biopsies collected from patients with psoriasis, Wu et al. examined the molecular basis of responses to IL-23 blockade. Patients who successfully responded to treatment showed reduced abundance of T17 cells and partial correction of psoriasis-specific gene expression. Even in patients displaying a strong clinical response to IL-23 blockade, a portion of the psoriatic T17 transcriptional identity persisted, although less than in poor responders. Conversely, successful response was associated with a greater than 90% attenuation of an IL-17–induced keratinocyte transcriptional signature. This study provides insight into single-cell resolution into the immunological drivers of cutaneous psoriasis and underlying clinical responses to IL-23 blockade. —Claire Olingy [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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